Sulindac reduces
colorectal cancer risk in genetically susceptible humans and animals. The molecular mechanisms underlying these effects are incompletely understood. Many studies suggest an important role for induction of apoptosis involving the mitochondrial pathway and the
death receptor pathway. Alternatively, mechanisms involving the APC-
beta-catenin-Wnt pathway have been suggested, possibly mediated by p21. We determined the effects of
sulindac on apoptosis and expression of
death receptor (DR)-4 and DR5,
beta-catenin, and p21 in normal-appearing colorectal epithelium. Biopsies were obtained before and after
sulindac treatment during two
chemoprevention studies. Patients (n = 18) with
hereditary nonpolyposis colorectal cancer (HNPCC) received 150 mg
sulindac bd for 4 weeks in a placebo-controlled crossover design. Patients (n = 6) with
familial adenomatous polyposis (FAP) received 150 mg
sulindac bd for 6 months. Apoptosis was assessed by M30 staining and expression patterns of DR4, DR5,
beta-catenin, and p21 were studied immunohistochemically. In HNPCC patients, apoptotic indices were similar following placebo and
sulindac. Also in FAP patients, apoptotic indices were not different after
sulindac compared with pretreatment values. Expression of DR4 and DR5 was observed in all samples with no consistent differences between placebo/baseline and
sulindac. Intensity of membranous
beta-catenin staining was lower in HNPCC samples following
sulindac compared with placebo (P < 0.001). Similar results were obtained in FAP samples (P < 0.01). p21 expressions before and after
sulindac treatment were similar in both patient groups. In conclusion,
sulindac inhibits
beta-catenin expression in normal colorectal epithelium from HNPCC and FAP patients without affecting apoptotic indices and DR4, DR5, and p21 expression.